Stable medicinal compositions containing 4,5-epoxymorphinan derivatives

ABSTRACT

A stable pharmaceutical composition includes a 4,5-epoxy-morphinan derivative, and includes at least one of the group consisting of a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, and a surfactant.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP98/03096 which has an Internationalfiling date of Jul. 10, 1998, which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a stable pharmaceutical compositionincluding 4,5-epoxy-morphinan derivative or pharmacologically acceptableacid-addition salts thereof. More particularly, the present inventionrelates to a stable pharmaceutical composition including4,5-epoxy-morphinan derivative which includes 4,5-epoxy-morphinanderivative as an effective component and includes a water solubleantioxidant, a fat soluble antioxidant, a synergist, a sugar, or asurfactant, and also relates to a method for stabilizing thepharmaceutical composition.

BACKGROUND ART

Morphine has a significant analgesic effect and is indicated forconditions such as postoperative pain and cancer pain. However, the drughas severe adverse reactions such as being addictive and causingrespiratory depression and constipation, which induces clinicalproblems. Therefore, morphine is an analgesic which demands meticulouscare.

Recently, it has become clear that opiate receptors may be classifiedinto three types, that is, μ, δ, and κ receptor, which function ascentral analgesic receptors. In addition, an opiate σ receptor has alsobeen elucidated which affects mental function.

The severe adverse reactions accompanied by administration of morphineare specific to the μ receptor agonist and to the σ receptor agonist.The δ receptor agonist and the κ receptor agonist seem not to show theabove-mentioned adverse reactions.

A 4,5-epoxy-morphinan derivative does not induce the severe adversereactions accompanied by the administration of morphine. In addition,the 4,5-epoxy-morphinan derivative is agonistic to the κ receptor or tothe δ receptor, and shows significant analgesic and diuretic activities.Furthermore, the 4,5-epoxy-morphinan derivative does not showcross-tolerance with morphine or the like, and does not show an affinityfor the σ receptor. Therefore, the 4,5-epoxy-morphinan derivative is apromising analgesic and a promising diuretic (WO93/15081).

However, the 4,5-epoxy-morphinan derivatives are chemically unstable toheat, light, and oxygen. Thus, means such as low-temperature storage,light protection, and displacement by an inert gas are necessary tostore them.

Therefore, it is significantly useful that a stable pharmaceuticalpreparation including these 4,5-epoxy-morphinan derivatives is prepared.

With respect to a conventional stabilizing method for morphine, that is,a morphinan derivative, for example, in Japanese Unexamined PatentPublication No. 2-160719, an attempt to improve stability of apharmaceutical preparation is made by adding a basic component tomorphine. In addition, a stabilized pharmaceutical composition(DE29719704) or the like is known in which an antioxidant such as sodiumthiosulfate or tocopherol is accompanied by naloxone. However, withrespect to a 4,5-epoxy-morphinan derivative, a stabilized compositionand a method of stabilization therefore has not been determinedheretofore.

An object of the present invention is to provide a stable pharmaceuticalcomposition including a 4,5-epoxy-morphinan derivative and also toprovide a method for stabilizing it.

DISCLOSURE OF INVENTION

The present invention relates to a pharmaceutical composition includinga 4,5-epoxy-morphinan derivative and at least one substance selectedfrom the group consisting of the following materials (1), (2), (3), (4)and (5).

(1) A water soluble antioxidant selected from the group consisting ofsodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite,L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate,cysteine, thioglycerol, and hydroxyquinoline sulfate.

(2) A fat soluble antioxidant selected from the group consisting ofpropyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol,ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, andmercaptobenzimidazole.

(3) A synergist selected from the group consisting of EDTA, saltsthereof, citric acid, salts thereof, and lecithin.

(4) A sugar selected from the group consisting of D-mannitol,D-sorbitol, xylitol, glucose, and fructose.

(5) A surfactant selected from the group consisting of sorbitansesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate,polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to stable pharmaceutical compositionsincluding a 4,5-epoxy-morphinan derivative and at least one componentselected from the group consisting of a water soluble antioxidant, a fatsoluble antioxidant, a synergist, a sugar, and a surfactant.

A 4,5-epoxy-morphinan derivative in accordance with the presentinvention can be prepared by the method disclosed in WO93/15081 and is acompound represented by the general formula (I) or pharmacologicallyacceptable acid-addition salts thereof:

wherein - - - is a double bond or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁷R⁸; R⁷ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R⁸ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R⁹; R⁹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or —N(R⁴)SO₂— (wherein X and Yare, independently of one another, NR⁴, S, or O; and R⁴ is a hydrogenatom, a straight-chain or branched-chain alkyl group having from 1 to 5carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴may be identical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group may be substituted with one ormore substituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupmay be replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon may be substitutedwith one or more substituents selected from the group consisting of analkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy grouphaving from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, achlorine atom, a bromine atom, an iodine atom, an amino group, a nitrogroup, a cyano group, a trifluoromethyl group, a trifluoromethoxy groupand a phenoxy group, and wherein one to three methylene groups of theacyclic unsaturated hydrocarbon may be replaced with carbonyl groups),or a straight-chain or branched-chain saturated or unsaturatedhydrocarbon containing from one to five thioether, ether and/or aminobonds and having from 1 to 14 carbon atoms (wherein no hetero atoms arebonded directly to A, and one to three methylene groups of thehydrocarbon may be replaced with carbonyl groups); and R⁵ is a hydrogenatom or an organic group having a basic skeleton selected from the groupconsisting of following formulas:

Organic Groups Represented by R⁵

wherein the organic group may have at least one substituent selectedfrom the group consisting of an alkyl group having from 1 to 5 carbonatoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxygroup having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom,a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitrogroup, a cyano group, an isothiocyanate group, a trifluoromethyl group,a trifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms or an alkanoylgroup having from 1 to 5 carbon atoms.

In the general formula (I), R¹ is preferably a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup, and more preferably a cyclopropylmethyl group or an allyl group.

R² and R³ are preferably a hydrogen atom, a hydroxy group, an acetoxygroup, or a methoxy group, independently.

A is preferably —N (R⁴)C(═O)—, —N(R⁴)C(═O)O—, —N(R⁴)—, or —N(R⁴)SO₂—(wherein R⁴ is a hydrogen atom, or a straight-chain or branched-chainalkyl group having from 1 to 5 carbon atoms). Among them A is morepreferably —N(R⁴)C(═O)— or —N(R⁴)C(═O)O— (wherein R⁴ is a hydrogen atom,or a straight-chain or branched-chain alkyl group having from 1 to 5carbon atoms).

B is preferably a straight-chain alkylene group having from 1 to 3carbon atoms, —CH═CH—, —C≡C—, —CH₂O— or —CH₂S—. Among them, B is morepreferably a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, or —C≡C—.

R⁵ is preferably a hydrogen atom or an organic group having a basicskeleton selected from the group consisting of the following basicformulas:

Organic Groups Represented by R⁵

wherein the organic group may be substituted with one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbonatoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxygroup, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an amino group, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup.

R⁶ is preferably a hydrogen atom.

17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinanhydrochloride (hereinafter referred to as “Compound 1”) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinanhydrochloride (hereinafter referred to as “Compound 2”) are particularlypreferred.

The pharmacologically acceptable acid-addition salts thereof areinorganic acid salts, such as chlorides, sulfates, nitrates,hydrobromides, hydroiodides, and phosphates; organic carboxylates, suchas acetates, lactates, citrates, oxalates, glutarates, malates,tartrates, fumarates, mandelates, maleates, benzoates, and phthalates;and organic sulfonates, such as methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, and camphor-sulfonates. Amongthem, chlorides, hydrobromides, phosphates, tartrates, malates, andmethanesulfonates are preferred, but of course the pharmacologicallyacceptable acid-addition salts thereof are not limited to thesecompounds.

With respect to a composition content of the 4,5-epoxy-morphinanderivative, that is, an effective component, any content may beavailable, even if the content of the effective component in apharmaceutical composition is sufficient for a treatment. For example,the content may range from 0.01 to 10000 μg/pharmaceutical composition.Ordinarily, the content preferably ranges from 0.1 to 1000μg/pharmaceutical composition.

In the present invention, sulfites, nitrites, ascorbic acids, thiolderivatives, hydroxyquinoline sulfate, or the like is used as a watersoluble antioxidant. Phenolic compounds, fat soluble vitamins, ascorbicacid esters, fat soluble vitamins, nordihydroguaiaretic acid,mercaptobenzimidazole, or the like is used as a fat soluble antioxidant.EDTA, salts thereof, citric acid, salts thereof, lecithin, or the likeis used as a synergist. The above-mentioned synergist shows a weakantioxidant effect by itself. However, the effect can be increased incombination with other antioxidants.

Specifically, a sulfite such as sodium sulfite, sodium hydrogensulfite,sodium pyrosulfite, or Rongalite, a nitrite such as sodium nitrite, aascorbic acid such as L-ascorbic acid or erysorbic acid, and a thiolderivative such as sodium thiosulfate, sodium thiomalate, cysteine,thioglycerol, or hydroxyquinoline sulfate is used as a water solubleantioxidant. Among them, sodium thiosulfate is most preferable.

A phenolic compound such as propyl gallate, butyl hydroxytoluene, orbutyl hydroxyanisole, a fat soluble vitamin such as tocopherol or a fatsoluble vitamin such as ascorbyl palmitate, ascorbyl stearate,nordihydroguaiaretic acid, or mercaptobenzimidazole is used as a fatsoluble antioxidant. Among them, propyl gallate, butyl hydroxytoluene orbutyl hydroxyanisole is preferable.

For example, EDTA, salts thereof, citric acid, salts thereof, lecithin,or the like is used as a synergist. With respect to salts, sodium salts,calcium salts, potassium salts, or magnesium salts are preferable. Amongthem, EDTA or citric acid is more preferable.

At least one selected from the group consisting of above-described watersoluble antioxidants, fat soluble antioxidants, and synergists is usedas an antioxidant. In addition, at least one sugar or at least onesurfactant can be mixed therein.

The content of the antioxidant ranges from 0.00001 to 10 percent byweight of the total pharmaceutical composition, preferably ranges from0.001 to 10 percent by weight of the total pharmaceutical composition,and more preferably 0.001 to 1 percent by weight of the totalpharmaceutical composition.

It is confirmed that the antioxidant is sufficiently effective when itis solved or dispersed in a solution, or when it is dispersed in asemisolid or in a solid. The antioxidant is effective for stabilizationof all dosage forms such as syrups, powders, fine granules, granules,tablets, hard capsules, soft capsules, injections, freeze-drying dosageforms, ointments, tapes, lotions, nose drops, ophthalmic solutions,aerosols, suspensions, emulsions, plasters, and suppositories.

Specifically, a sugar used in the present invention, for example, isD-mannitol, D-sorbitol, xylitol, glucose, maltose, fructose, sucrose, orwhite soft sugar.

Preferably, D-mannitol, D-sorbitol, xylitol, glucose, or fructose isused alone or used in a mixture of at least two thereof. Furthermore, atleast one of water soluble antioxidants, fat soluble antioxidants,synergists, and surfactants can be mixed therein.

The content of the sugar ranges from 0.01 to 20 percent by weight of thetotal pharmaceutical composition, preferably ranges from 0.1 to 20percent by weight of the total pharmaceutical composition, and morepreferably 1 to 20 percent by weight of the total pharmaceuticalcomposition.

It is confirmed that addition of sugars is particularly useful forstabilization of injections. In addition, it has been shown that when awater soluble antioxidant, a fat soluble antioxidant, or a synergist asan antioxidant is added, a greater stabilization effect can be obtained.Among them, D-mannitol, D-sorbitol, xylitol, and glucose are useful forstabilization of the injections. With respect to the accompanyingantioxidant, sodium thiosulfate, that is, a water soluble antioxidantand citric acid, that is, a synergist, are particularly preferable.

Specifically, a surfactant used in the present invention, for example,is sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glycerylmyristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene laurylether.

Preferably, glyceryl myristate or polyoxyethylene nonylphenyl ether isused alone or used as a mixture of at least two thereof. Furthermore, atleast one of water soluble antioxidants, fat soluble antioxidants,synergists, and sugars can be mixed therein.

The content of the surfactant ranges from 0.0001 to 20 percent by weightof the total pharmaceutical composition, preferably ranges from 0.001 to20 percent by weight of the total pharmaceutical composition, and morepreferably 0.01 to 10 percent by weight of the total pharmaceuticalcomposition.

It is confirmed that addition of the surfactant is particularly usefulfor stabilization of external preparations such as ointments, gels,tapes, lotions, nose drops, ophthalmic solutions, aerosols, andsuppositories. In addition, it is shown that when a water solubleantioxidant, a fat soluble antioxidant, or a synergist as an antioxidantis added, a greater stabilization effect can be obtained. Among them,glyceryl myristate and polyoxyethylene nonylphenyl ether are useful forstabilization of the external preparations. With respect to theaccompanying antioxidant, citric acid, that is, a synergist, isparticularly preferable.

An available additive such as vehicles, binders, thickener, solubilizer,solvents, isotonizing agents, buffers, preservatives, or bases may beadded to the pharmaceutical compositions in accordance with the presentinvention, if necessary.

The additives in the present invention are not particularly limited,even though they are pharmaceutically acceptable. Examples of a vehicleare lactose, white soft sugar, sucrose, sorbitol, microcrystallinecellulose, corn starch, gelatin, dextrans and the like. Examples of abinder are hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinyl pyrrolidone, methyl cellulose, and the like. Examples of athickener are gum arabic, sodium hyaluronate, xanthan gum, and the like.Examples of a solvent are water, ethanol, propylene glycol, polyethyleneglycol, Polysorbate 80, glycerin, soybean oil and the like. Examples ofan isotonizing agent are sodium chloride, D-mannitol, xylitol, glucoseand the like. Examples of a solubilizer are cyclodextrin and the like.Examples of a nonionic surfactant are polyoxyethylene hydrogenatedcastor oil, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate,glyceryl oleate, glyceryl myristate, polyoxyethylene lauryl ether,polyoxyethylene nonylphenyl ether, and the like. Examples of a bufferare tartaric acid, citric acid, maleic acid, phosphoric acid, succinicacid, lactic acid, acetic acid, sodium hydrogencarbonate, boric acid,sodium borate, magnesium oxide, magnesium hydroxide, and the like.Examples of a preservative are methyl paraoxybenzoate, ethylparaoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate,benzalkonium chloride, and the like. Examples of a base are whitepetrolatum, Witepsol, Plastibase, liquid paraffin, and the like.

The pharmaceutical compositions in accordance with the present inventionare not particularly limited, even though they have pharmaceuticallyacceptable dosage forms for administration. The pharmaceuticalcompositions in accordance with the present invention are available forall dosage forms such as syrups, powders, fine granules, granules,tablets, hard capsules, soft capsules, injections, freeze-drying dosageforms, ointments, gels, tapes, lotions, nose drops, ophthalmicsolutions, aerosols, suspensions, emulsions, plasters, andsuppositories.

EXAMPLES

Advantages of the present invention will become clear from the followingdescription of examples. However, it is to be understood that theinvention is not limited thereto.

Example 1

In measuring flasks, aqueous solutions containing Compound 1 (10 μg/mL)which were added a predetermined concentration of a variety ofantioxidants, and an aqueous solution containing the compound with noadditives were prepared. Test 1, Test 2, and Comparative Example areshown in Table 1.

TABLE 1 Drug Example 1 Dosage Form Content Antioxidant Additive RateComparative Aqueous 10 μg/mL None Example solution Test 1 Aqueous 10μg/mL Citric acid 0.10% solution Test 2 Aqueous 10 μg/mL Sodium 0.10%solution thiosulfate

Stability test: The aqueous solutions of Test 1, Test 2, and Comparativeexample were sealed in ampoules. Then, after storing them at atemperature of 80° C. for five days, the concentrations of Compound 1were measured using a HPLC method (an UV method). The residual rateswere calculated, so that stability of the aqueous solutions wasestimated.

TABLE 2 Additive Storage Residual Example 1 Antioxidant Rate ConditionsRate (%) Comparative None Seal/80° C./5 d 41.4 Example Test 1 Citricacid 0.10% Seal/80° C./5 d 93.5 Test 2 Sodium 0.10% Seal/80° C./5 d 90.8thiosulfate

As shown in Table 2, the residual rates of Test 1 and Test 2 to whichthe antioxidant was added by 0.1% were higher than that of ComparativeExample to which no antioxidant was added, so that a significantstabilizing effect on Compound 1 was shown.

Example 2

As shown in Prescription Example 1, injections were prepared by adding apredetermined amount of an isotonizing agent to Compound 1 (10 μg/mL).Tests 1 to 4 and Comparative Example are shown in Table 3.

(Prescription Example 1) Injection

Compound 1 1 mg Isotonizing agent 0.9 to 5 g Water for injection Balancevolume Total 100 mL

TABLE 3 Drug Isotonizing Additive Example 2 Dosage Form Content AgentRate Comparative Injection 10 μg/mL Sodium chloride 0.90% Example Test 1Injection 10 μg/mL Glucose 5.00% Test 2 Injection 10 μg/mL Xylitol 5.00%Test 3 Injection 10 μg/mL Mannitol 5.00% Test 4 Injection 10 μg/mLD-sorbitol 5.00%

Stability test: After the aqueous solutions of Tests 1 to 4, andComparative Example were subjected to nitrogen bubbling, they weresealed in ampoules. Then, after storage at a temperature of 80° C. forseven days, the residual rates of Compound 1 were measured using a HPLCmethod (an UV method). Thus, stability after accelerated storage wasestimated.

TABLE 4 Isotonizing Storage Residual Example 2 Agent Additive RateConditions Rate (%) Comparative Sodium 0.90% Seal/80° C./7 d 66.6Example chloride Test 1 Glucose 5.00% Seal/80° C./7 d 90.3 Test 2Xylitol 5.00% Seal/80° C./7 d 97.9 Test 3 Mannitol 5.00% Seal/80° C./7 d98.9 Test 4 D-sorbitol 5.00% Seal/80° C./7 d 97.4

As shown in Table 4, the residual rates of Tests 1 to 4 weresignificantly higher than that of Comparative Example to which sodiumchloride as the isotonizing agent was added. Therefore, with respect tothe accelerated storage of the injections, sugars as isotonizing agentsshowed significant stabilizing effects on Compound 1.

Example 3

As shown in Prescription Example 2, injections were prepared by adding apredetermined amount of sodium thiosulfate to a 5% aqueous solution ofmannitol containing Compound 1 (10 μg/mL) and a injection to which nosodium thiosulfate was added was also prepared. Tests 1 to 3 andComparative Example are shown in Table 5.

(Prescription Example 2) Injection

Compound 1 1 mg Sodium thiosulfate 0 to 1 g Mannitol 5 g Water forinjection Balance volume Total 100 mL

TABLE 5 Additive Example 3 Dosage Form Drug Content Antioxidant RateComparative Injection 10 μg/mL None Example Test 1 Injection 10 μg/mLSodium 0.10% thiosulfate Test 2 Injection 10 μg/mL Sodium 0.50%thiosulfate Test 3 Injection 10 μg/mL Sodium 1.00% thiosulfate

Stability test: The aqueous solutions of Tests 1 to 3, and that ofComparative Example were sealed in ampoules. Then, after sterilizationby heating at a temperature of 120° C. for 60 minutes, the purities ofCompound 1 in the samples were measured using a HPLC method (an UVmethod). Thus, pharmaceutical stability after sterilization wasestimated.

TABLE 6 Additive Purity Example 3 Antioxidant Rate Storage Conditions(%) Comparative None Seal/120° C./60 min 98.95 Example Test 1 Sodium0.10% Seal/120° C./60 min 99.57 thiosulfate Test 2 Sodium 0.50%Seal/120° C./60 min 99.44 thiosulfate Test 3 Sodium 1.00% Seal/120°C./60 min 99.53 thiosulfate

As shown in Table 6, the purities of Tests 1 to 3 were significantlyhigher than that of Comparative Example to which no antioxidant wasadded. With respect to the sterilization process of the injections,sodium thiosulfate showed a significant stabilizing effect onCompound 1. The difference of the effects due to the amounts of thesodium thiosulfate was not seen in the range of 0.1 to 1.0%, and anyadditive amount showed the same stabilizing effect.

Example 4

Aqueous solutions containing Compound 1 and a predetermined amount ofantioxidants, or an aqueous solution, to which no antioxidant was added,were added dropwise and mixed to a mixture of lactose and Avicel PH101,so that granulated substances were obtained. After drying theabove-mentioned substances at a temperature of 40° C. for 12 hours, sothat the granules shown in Prescription Example 3 were prepared. Tests 1to 9 and Comparative Example are shown in Table 7.

(Prescription Example 3) Granule

Compound 1 100 mg Sodium thiosulfate 0 to 1 g Avicel PH-101 31 g LactoseBalance volume Total 100 g

TABLE 7 Dosage Additive Example 4 Form Drug Content Antioxidant RateComparative Granule 100 μg/100 mg None Example Test 1 Granule 100 μg/100mg EDTA 0.10% Test 2 Granule 100 μg/100 mg Citric acid 0.10% Test 3Granule 100 μg/100 mg Propyl gallate 0.10% Test 4 Granule 100 μg/100 mgButyl 0.10% Hydroxyanisole Test 5 Granule 100 μg/100 mg Tocopherol 0.10%Test 6 Granule 100 μg/100 mg Sodium 0.10% thiosulfate Test 7 Granule 100μg/100 mg Sodium 0.20% thiosulfate Test 8 Granule 100 μg/100 mg Sodium0.50% thiosulfate Test 9 Granule 100 μg/100 mg Sodium 1.00% thiosulfate

Stability test: Immediately after manufacturing the granules of Tests 1to 9 and that of Comparative Example, the purities of Compound 1 weremeasured using a HPLC method (an UV method). Thus, pharmaceuticalstability was estimated.

TABLE 8 Additive Purity Example 4 Antioxidant Rate Storage Conditions(%) Comparative None Immediately after 98.48 Example Manufacturing Test1 EDTA 0.10% Immediately after 98.75 Manufacturing Test 2 Citric acid0.10% Immediately after 98.56 Manufacturing Test 3 Propyl gallate 0.10%Immediately after 99.33 Manufacturing Test 4 Butyl 0.10% Immediatelyafter 98.62 Hydroxyanisole Manufacturing Test 5 Tocopherol 0.10%Immediately after 99.20 Manufacturing Test 6 Sodium 0.10% Immediatelyafter 99.49 thiosulfate Manufacturing Test 7 Sodium 0.20% Immediatelyafter 99.49 thiosulfate Manufacturing Test 8 Sodium 0.50% Immediatelyafter 99.30 thiosulfate Manufacturing Test 9 Sodium 1.00% Immediatelyafter 98.99 thiosulfate Manufacturing

As shown in Table 8, the purities of the compound in the granules ofTests 1 to 9 were significantly higher than that of Comparative Exampleto which no antioxidant was added. Thus, the stabilizing effects onCompound 1 were also shown in the granules. In addition, when thedifference of the effects due to the amounts of the sodium thiosulfatewas studied in Tests 6 to 9, the highest stabilizing effect can be seenin the range of 0.1 to 0.2%.

Example 5

Aqueous solutions containing Compound 1 and a predetermined amount ofantioxidants, or an aqueous solution, to which no antioxidant was added,were added dropwise and mixed to a mixture of lactose, Avicel PH101, andHPC-SL, so that granulated substances were obtained. After drying theabove-mentioned substances at a temperature of 40° C. for 12 hours,sieving them, mixing with magnesium stearate, and compressing tablets,the tablets shown in Prescription Example 4 were prepared. Tests 1 andComparative Example are shown in Table 9.

(Prescription Example 4) Tablet

Compound 1 100 mg Sodium thiosulfate 0 to 1 g Avicel PH-101 30 g HPC-SL3 g Magnesium stearate 0.5 g Lactose Balance volume Total 100 g

TABLE 9 Additive Example 5 Dosage Form Drug Content Antioxidant RateComparative Tablet 100 μg/tablet None Example Test 1 Tablet 100μg/tablet Sodium 0.10% thiosulfate

Stability test: After the tablets of Test 1 and Comparative Example weresealed in bottles, they were stored at a temperature of 40° C. and at arelative humidity (R.H.) by 75% for three months. Then, the residualrates were measured using a HPLC method (an UV method), so thatpharmaceutical stability was estimated.

TABLE 10 Additive Purity Example 5 Antioxidant Rate Storage Conditions(%) Comparative None Seal/40° C./75% 98.12 Example R.H./3 m Test 1Sodium 0.10% Seal/40° C./75% 99.20 thiosulfate R.H./3 m

As shown in Table 10, the residual rates of Test 1 was higher than thatof Comparative Example to which no antioxidant was added, so that withrespect to a tablet, a significant stabilizing effect on Compound 1 wasalso seen.

Example 6

Aqueous solutions containing Compound 1 and a predetermined amount ofantioxidants, or an aqueous solution, to which no antioxidant was added,were dissolved in Polyethylene glycol 400, so that filling fluids forsoft capsules shown in Prescription Example 5 were prepared. Tests 1 to3 and Comparative Example are shown in Table 11.

(Prescription Example 5) Filling Fluid For Soft Capsules

Compound 1 40 mg Sodium thiosulfate 0 to 0.1 g Purified water 2 gPolyethylene glycol 400 Balance volume Total 100 g

TABLE 11 Dosage Additive Example 6 Form Drug Content Antioxidant RateComparative Filling fluid 40 μg/100 mg None 0.00% Example for softcapsules Test 1 Filling fluid 40 μg/100 mg Sodium 0.01% for softthiosulfate capsules Test 2 Filling fluid 40 μg/100 mg Sodium 0.05% forsoft thiosulfate capsules Test 3 Filling fluid 40 μg/100 mg Sodium 0.10%for soft thiosulfate capsules

Stability test: After the filling fluids for the soft capsules of Test 1to 3 and that of Comparative Example were sealed in ampoules, thefilling fluids for the soft capsules were stored at a temperature of 80°C. for one week. Then, the residual rates of compound 1 were measuredusing a HPLC method (an UV method), so that pharmaceutical stability ofthe filling fluid was estimated.

TABLE 12 Additive Residual Example 6 Antioxidant Rate Storage ConditionsRate (%) Comparative None 0.00% Seal/80 ° C./1 w 19.3 Example Test 1Sodium 0.01% Seal/80 ° C./1 w 23.4 thiosulfate Test 2 Sodium 0.05%Seal/80 ° C./1 w 88.3 thiosulfate Test 3 Sodium 0.10% Seal/80 ° C./1 w85.1 thiosulfate

As shown in Table 12, the residual rates of Test 1 to 3 were higher thanthat of Comparative Example to which no antioxidant was added, so thatwith respect to the above-described filling fluids a significantstabilizing effect on Compound 1 was shown. In addition, the differenceof the effects due to the amounts of the sodium thiosulfate was studied.It has been clear that the greater the additional amount, the higher thestabilizing effect.

Example 7

The filling fluid for the soft capsules of Test 1 and that ofComparative Example were degassed by nitrogen bubbling. Then, 100 mg ofthe filling fluid for the soft capsule was packed in the gelatin capsuleshown in Prescription Example 6, so that the soft capsule was prepared.Test 1 and Comparative Example are shown in Table 13.

(Prescription Example 6) Gelatin Capsule For Soft Capsules

Gelatin 21 g Gelatin succinate 21 g Glycerin 23 g Titanium oxide 0.7 gPurified water Balance volume Total 100 g

TABLE 13 Dosage Additive Example 7 Form Drug Content Antioxidant RateComparative Soft capsule 40 μg/capsule None 0.00% Example Test 1 Softcapsule 40 μg/capsule Sodium 0.10% thiosulfate

Stability test: After the capsule of Test 1 and that of ComparativeExample were sealed in bottles, the capsules were stored at atemperature of 40° C. and at a R.H. by 75% for one month. Then, theresidual concentrations of the drug were measured using a HPLC method(an UV method), so that stability of the soft capsule was estimated.

TABLE 14 Additive Residual Example 7 Antioxidant Rate Storage ConditionsRate (%) Comparative None 0.00% Seal/40° C./75% 98.8 Example R.H./1 mTest 1 Sodium 0.10% Seal/40° C./75% 99.1 thiosulfate R.H./1 m

As shown in Table 14, the residual rate of Test 1 was higher than thatof Comparative Example to which no antioxidant was added, so that withrespect to a soft capsule, a significant stabilizing effect on Compound1 due to the antioxidant was seen.

Example 8

Hydroxypropylmethylcellulose as a gelatinizing agent, Polyethyleneglycol 4000 as a humectant, and ethyl paraoxybenzoate and butylparaoxybenzoate as preservatives were dissolved in an aqueous solutioncontaining Compound 1 and a predetermined amount of antioxidants, orwere dissolved in an aqueous solution to which no antioxidant was added.Thus, aqueous gels shown in Prescription Example 7 were prepared. Tests1 and Comparative Example are shown in Table 15.

(Prescription Example 7) Aqueous Gel

Compound 1 1 mg Hydroxypropylmethylcellulose 2 g Polyethylene glycol4000 15 g Sodium thiosulfate 0 to 0.1 g Ethyl paraoxybenzoate 0.03 gButyl paraoxybenzoate 0.02 g Purified water Balance volume Total 100 g

TABLE 15 Additive Example 8 Dosage Form Drug Content Antioxidant RateComparative Aqueous gel 10 μg/g None 0.00% Example Test 1 Aqueous gel 10μg/g Sodium 0.10% thiosulfate

Stability test: After the aqueous gel of Test 1 and that of ComparativeExample were sealed in aluminized tube, the aqueous gels were stored ata temperature of 60° C. and at a R.H. by 75% for one month. Then, thepurities of Compound 1 in the aqueous gels were measured using a HPLCmethod (an UV method), so that stability of the aqueous gel wasestimated.

TABLE 16 Additive Purity Example 8 Antioxidant Rate Storage Conditions(%) Comparative None 0.00% Seal/60° C./75% 19.3 Example R.H./l m Test 1Sodium 0.10% Seal/60° C./75% 99.6 thiosulfate R.H./l m

As shown in Table 16, the purity of Test 1, to which sodium thiosulfatewas added at a concentration of 0.1%, was higher than that ofComparative Example, to which sodium thiosulfate was not added, duringstorage under a severe condition. Thus, with respect to an aqueous gel,a significant stabilizing effect on Compound 1 due to sodium thiosulfatewas seen.

Example 9

As shown in Prescription Example 8, Compound 1 was dissolved in a heatedsurfactant, and the mixture was mixed with liquid paraffin and whitepetrolatum. Thus, petrolatum ointments were obtained. Tests 1 to 6 andComparative Example are shown in Table 17.

(Prescription Example 8) Petrolatum Ointment

Compound 1 1 mg Surfactant 5 g Liquid paraffin 15 g White petrolatumBalance volume Total 100 g

TABLE 17 Addi- Drug tive Example 9 Dosage Form Content Solubilizer RateComparative Petrolatum 10 μg/g Glyceryl monooleate 5.00% Exampleointment Test 1 Petrolatum 10 μg/g Sorbitan 5.00% ointment sesquioleateTest 2 Petrolatum 10 μg/g Sorbitan monolaurate 5.00% ointment Test 3Petrolatum 10 μg/g Sorbitan 5.00% ointment monopalmitate Test 4Petrolatum 10 μg/g Polyoxyethylene (2) 5.00% ointment lauryl ether Test5 Petrolatum 10 μg/g Glyceryl 5.00% ointment monomyristate Test 6Petrolatum 10 μg/g polyoxyethylene (3) 5.00% ointment nonylphenyl ether

Stability test during manufacturing: Yields of the major degradationproducts (N-oxides) in the ointments of Test 1 to 6 and that ofComparative Example were measured using a HPLC method (an UV method)immediately after the preparation therefor. Thus, stability duringmanufacturing was estimated.

TABLE 18 Yield of Addi- major tive Storage degradation Example 9Solubilizer Rate Conditions product (%) Comparative Glyceryl 5.00%Stability 5.6 Example monooleate immediately after manufacturing Test 1Sorbitan 5.00% Stability 1 sesquioleate immediately after manufacturingTest 2 Sorbitan 5.00% Stability 0.7 monolaurate immediately aftermanufacturing Test 3 Sorbitan 5.00% Stability 0.8 monopalmitateimmediately after manufacturing Test 4 Polyoxyethylene 5.00% Stability1.6 (2) lauryl ether immediately after manufacturing Test 5 Glyceryl5.00% Stability 0 monomyristate immediately after manufacturing Test 6polyoxyethylene 5.00% Stability 0 (3) nonylphenyl immediately etherafter manufacturing

As shown in Table 18, the yields of the major degradation products ofTests 1 to 6 were lower than that of Comparative Example to which asurfactant was added. In particular, the addition of glycerylmonomyristate or polyoxyethylene nonylphenyl, that is, Test 5 or 6,respectively, showed a significant stabilizing effect.

Example 10

As shown in Prescription Example 9, Compound 1 and citric acid weredissolved in heated glycerin monomyristate, and the mixture was mixedwith liquid paraffin and white petrolatum. Thus, petrolatum ointments towhich a predetermined amount of citric acid was added, and a petrolatumointment to which citric acid was not added were obtained. Tests 1, Test2, and Comparative Example are shown in Table 19.

(Prescription Example 9) Petrolatum Ointment

Compound 1 1 mg Glyceryl monomyristate 5 g Citric acid 0 to 0.1 g Liquidparaffin 15 g White petrolatum Balance volume Total 100 g

TABLE 19 Drug Additive Example 10 Dosage Form Content Antioxidant RateComparative Petrolatum 10 μg/g None — Example ointment Test 1 Petrolatum10 μg/g Citric acid 0.001% ointment Test 2 Petrolatum 10 μg/g Citricacid 0.10%  ointment

Stability test: After the ointments of Test 1, Test 2 and ComparativeExample were sealed in aluminized tubes, the ointments were stored at atemperature of 60° C. and at a R.H. by 75% for a half month. Then, thepurities of Compund 1 in the ointments were measured using a HPLC method(an UV method), so that stability of the ointment was estimated.

TABLE 20 Additive Purity Example 10 Antioxidant Rate Storage Conditions(%) Comparative None 0.00% Seal/60° C./75% 89.4 Example R.H./0.5 m Test1 Citric acid  0.001% Seal/60° C./75% 98.4 R.H./0.5 m Test 2 Citric acid0.10% Seal/60° C./75% 96.2 R.H./0.5 m

As shown in Table 20, the purities of the drug of Tests 1 and 2 werehigher than that of Comparative Example to which citric acid was notadded. With respect to a petrolatum ointment, citric acid (a synergist)showed a significant stabilizing effect on Compound 1.

Example 11

As shown in Prescription Example 10, injections were prepared by addinga predetermined amount of an isotonizing agent to Compound 2 (50 μg/mL).Tests 1 to 3 and Comparative Example are shown in Table 21.

(Prescription Example 10) Injection

Compound 2 5 mg Isotonizing agent 0.9 to 5 g Water for injection Balancevolume Total 100 mL

TABLE 21 Drug Isotonizing Additive Example 11 Dosage Form Content AgentRate Comparative Injection 50 μg/mL Sodium chloride 0.90% Example Test 1Injection 50 μg/mL Glucose 5.00% Test 2 Injection 50 μg/mL Xylitol 5.00%Test 3 Injection 50 μg/mL Mannitol 5.00%

Stability test: The aqueous solutions of Tests 1 to 3, and that ofComparative Example were sealed in ampoules. After sterilization byhigh-pressure steam at a temperature of 121° C. for 30 minutes, theresidual rates of Compound 2 in the samples were measured using a HPLCmethod (an UV method). Thus, pharmaceutical stability aftersterilization was estimated.

TABLE 22 Example Isotonizing Additive Storage Residual 11 Agent RateConditions Rate (%) Com- Sodium 0.90% Seal/121° C./30 mim 94.7 parativechloride Example Test 1 Glucose 5.00% Seal/121° C./30 mim 100.0 Test 2Xylitol 5.00% Seal/121° C./30 mim 98.0 Test 3 Mannitol 5.00% Seal/121°C./30 mim 100.0

As shown in Table 22, the residual rates of Tests 1 to 3 weresignificantly higher than that of Comparative Example to which sodiumchloride as an isotonizing agent was added. Therefore, with respect tothe high-pressure steam sterilization process, sugars as isotonizingagents showed significant stabilizing effects on Compound 2.

Industrial Applicability

As shown in the results of the above-described examples, apharmaceutical composition including a 4,5-epoxy-morphinan derivative inaccordance with the present invention is a stable pharmaceuticalpreparation in which stability of the 4,5-epoxy-morphinan derivative isimproved. Furthermore, the stability thereof is significantly improvedby optimizing compound ratio and ingredients thereof. In addition, sincea stabilization effect is seen, in spite of variations in the dosageform of the drug, it is suggested that the handling during manufacturingthe drug and storing thereof can be improved, and effectiveness,stability, and handling during administration can also be improved.Furthermore, a variety of dosage forms and administration routes can beselected, and indications for treatments for various diseases can beexpanded.

What is claimed is:
 1. A pharmaceutical composition comprising, a4,5-epoxy-morphinan derivative and at least one substance selected fromthe group consisting of the following materials (1), (2), (3), (4) and(5): (1) a water soluble antioxidant selected from the group consistingof sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite,Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid, sodiumthiosulfate, sodium thiomalate, cysteine, thioglycerol, andhydroxyquinoline sulfate; (2) a fat soluble antioxidant selected fromthe group consisting of propyl gallate, butyl hydroxytoluene, butylhydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate,nordihydroguaiaretic acid, and mercaptobenzimidazole; (3) a synergistselected from the group consisting of EDTA, salts thereof, citric acid,salts thereof, and lecithin; (4) a sugar selected from the groupconsisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose;and (5) a surfactant selected from the group consisting of sorbitansesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate,polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether,wherein the 4,5-epoxy-morphinan derivative is a compound represented bythe general formula (I) or pharmacologically acceptable salts thereof:

wherein - - - is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁷R⁸; R⁷ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R⁸ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms or —C(═O)R⁹; R⁹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or —N(R⁴)SO₂— (wherein X and Yare, independently of one another, NR⁴, S, or O; and R⁴ is a hydrogenatom, a straight-chain or branched-chain alkyl group having from 1 to 5carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴is identical or different in the formula); B is a valence bond, astraight-chain or branched chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted withone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds having from 2 to 14 carbon atoms(wherein the acyclic unsaturated hydrocarbon is optionally substitutedwith one or more substituents selected from the group consisting of analkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy grouphaving from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, achlorine atom, a bromine atom, an iodine atom, an amino group, a nitrogroup, a cyano group, a trifluoromethyl group, a trifluoromethoxy groupand a phenoxy group, and wherein one to three methylene groups of theacyclic unsaturated hydrocarbon is optionally replaced with carbonylgroups), or a straight-chain or branched-chain saturated or unsaturatedhydrocarbon containing from one to five thioether, ether, and/or aminobonds and having from 1 to 14 carbon atoms (wherein no hetero atoms arebonded directly to A, and one to three methylene groups of thehydrocarbon is optionally replaced with carbonyl groups); and R⁵ is ahydrogen atom or an organic group having a basic skeleton selected fromthe group consisting of the following basic formulas:

organic groups represented by R⁵ wherein the organic group hasoptionally at least one substituent selected from the group consistingof an alkyl group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoylgroup having from 1 to 5 carbon atoms.
 2. A pharmaceutical compositionaccording to claim 1, wherein in the general formula (I), R¹ is a methylgroup, an ethyl group, a propyl group, a butyl group, an isobutyl group,a cyclopropylmethyl group, an allyl group, a benzyl group, or aphenethyl group; R² and R³ are, independently of one another, a hydrogenatom, a hydroxy group, an acetoxy group, or a methoxy group; A is—N(R⁴)C(═O)—, —N(R⁴)C(═O)O—, —N(R⁴)—, or —N(R⁴)SO₂— (wherein R⁴ is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms); B is a straight-chain alkylene group havingfrom 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH₂O— or —CH₂S—; R⁵ is thesame as in claim 1; and R⁶ is a hydrogen atom.
 3. A pharmaceuticalcomposition according to claim 2, wherein in the general formula (I), R⁵is a hydrogen atom or an organic group having a basic skeleton selectedfrom the group consisting of the following basic formulas:

Organic Groups Represented by R⁵ wherein the organic group is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group.
 4. A pharmaceuticalcomposition according to claim 3, wherein in the general formula (I), R¹is a cyclopropylmethyl group or an allyl group; A is —N(R⁴)C(═O)— or—N(R⁴)C(═O)O— (wherein R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms); and B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,or —C≡C—.
 5. The pharmaceutical composition according to any one ofclaims 1, 2, 3, or 4, wherein each content of the water-solubleantioxidant, the fat soluble antioxidant, and the synergist ranges from0.00001 to 10 percent by weight of the total pharmaceutical composition.6. An injection preparation comprising: a compound represented by thegeneral formula (I) or pharmacologically acceptable acid-addition saltsthereof:

wherein - - - is a double bond or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁷R⁸; R⁷ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R⁸ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C((═O)R⁹; R⁹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or —N(R⁴)SO₂— (wherein X and Yare, independently of one another, NR⁴, S, or O; and R⁴ is a hydrogenatom, a straight-chain or branched-chain alkyl group having from 1 to 5carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴is identical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted withone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the following basicformulas:

Organic Groups Represented by R⁵ wherein the organic group hasoptionally at least one substituent selected from the group consistingof an alkyl group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoylgroup having from 1 to 5 carbon atoms; and at least one sugar selectedfrom the group consisting of D-mannitol, D-sorbitol, xylitol, glucose,and fructose.
 7. An injection preparation according to claim 6, furthercomprising, at least one substance selected from the group consisting ofthe following materials (1), (2), and (3): (1) a water solubleantioxidant selected from the group consisting of sodium sulfite, sodiumhydrogensulfite, sodium pyrosulfite, Rongalite, sodium nitrite,L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate,cysteine, thioglycerol, and hydroxyquinoline sulfate; (2) a fat solubleantioxidant selected from the group consisting of propyl gallate, butylhydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate,ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole;and (3) a synergist selected from the group consisting of EDTA, saltsthereof, citric acid, salts thereof, and lecithin.
 8. An externalpreparation comprising: a compound represented by the general formula(I) or pharmacologically acceptable acid-addition salts thereof:

wherein - - - is a double bond or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁷R⁸; R⁷ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R⁸ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R⁹; R⁹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or —N(R⁴)SO₂— (wherein X and Yare, independently of one another, NR⁴, S, or O; and R⁴ is a hydrogenatom, a straight-chain or branched-chain alkyl group having from 1 to 5carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴is identical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted withone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the following basicformulas:

Organic Groups Represented by R⁵ wherein the organic group hasoptionally at least one substituent selected from the group consistingof an alkyl group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoylgroup having from 1 to 5 carbon atoms; and at least one surfactantselected from the group consisting of sorbitan sesquioleate, sorbitanlaurate, sorbitan palmitate, glyceryl myristate, polyoxyethylenenonylphenyl ether, and polyoxyethylene lauryl ether.
 9. An externalpreparation according to claim 8, further comprising, at least onesubstance selected from the group consisting of the following materials(1), (2), and (3): (1) a water soluble antioxidant selected from thegroup consisting of sodium sulfite, sodium hydrogensulfite, sodiumpyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid,sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, andhydroxyquinoline sulfate; (2) a fat soluble antioxidant selected fromthe group consisting of propyl gallate, butyl hydroxytoluene, butylhydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate,nordihydroguaiaretic acid, and mercaptobenzimidazole; and (3) asynergist selected from the group consisting of EDTA, salts thereof,citric acid, salts thereof, and lecithin.
 10. A method for stabilizing a4,5-epoxy-morphinan derivative, wherein at least one substance selectedfrom the group consisting of the following materials (1), (2), (3), (4),and (5) is used: (1) a water soluble antioxidant selected from the groupconsisting of sodium sulfite, sodium hydrogensulfite, sodiumpyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erysorbic acid,sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, andhydroxyquinoline sulfate; (2) a fat soluble antioxidant selected fromthe group consisting of propyl gallate, butyl hydroxytoluene, butylhydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate,nordihydroguaiaretic acid, and mercaptobenzimidazole; (3) a synergistselected from the group consisting of EDTA, salts thereof, citric acid,salts thereof, and lecithin; (4) a sugar selected from the groupconsisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose;and (5) a surfactant selected from the group consisting of sorbitansesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate,polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether,wherein the 4,5-epoxy-morphinan composition is a compound represented bythe general formula (I) or pharmacologically acceptable salts thereof:

wherein - - - is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁷R⁸; R⁷ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R⁸ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R⁹; R⁹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or N(R⁴)SO₂— (wherein X and Y are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ isidentical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted withone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having form 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the following basicformulas:

organic groups represented by R⁵ wherein the organic group hasoptionally at least one substituent selected from the group consistingof an alkyl group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms, or an alkanoylgroup having from 1 to 5 carbon atoms.
 11. The method for stabilizingthe 4,5-epoxy-morphinan derivative according to claim 10, wherein in thegeneral formula (I), R¹ is a methyl group, an ethyl group, a propylgroup, a butyl group, an isobutyl group, a cyclopropylmethyl group, anallyl group, a benzyl group, or a phenethyl group; R² and R³ are,independently of one another, a hydrogen atom, a hydroxy group, anacetoxy group, or a methoxy group; A is —N(R⁴)C(═O)—, —N(R⁴)C(═O)O —,—N(R⁴)—, or —N(R⁴)SO₂— (wherein R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms); B is a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, —C≡C—, —CH₂O— or CH₂S—; R⁵ is the same as in claim 11;and R⁶ is a hydrogen atom.
 12. A method for stabilizing a4,5-epoxy-morphinan derivative according to claim 11, wherein in thegeneral formula (I), R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the following basicformulas:

Organic Groups Represented by R⁵ wherein the organic group is optionallysubstituted with one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, an isothiocyanate group, a trifluoromethyl group, atrifluoromethoxy group, and a methylenedioxy group.
 13. A method forstabilizing a 4,5-epoxy-morphinan derivative according to claim 12,wherein in the general formula (I), R¹ is a cyclopropylmethyl group oran allyl group; A is —N(R⁴)C(═O)— or —N(R⁴)C(═O)O— (wherein R⁴ is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms); and B is a straight-chain alkylene grouphaving from 1 to 3 carbon atoms, —CH═CH—, or —C≡C—.